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PHYSIOLOGY 03028 WEEK 10: DIGESTIVE SYSTEM; INTRODUCTION TO HORMONES

Cormack: Ch. 8; Guyton and Hall, Chs. 62-72, 74; Michael and Rovick, Unit 9; van Wysberghe and Cooley, Cases 19-21. 3/27/00 W. Crone (303 FTZ, 629-7439, cronewil@hvcc.edu, http://www.hvcc.edu/academ/faculty/crone/index.html

possible web sites: http://www.flint.umich.edu/departments/PT/ptp522/gianat/index.htm

(Power Point slides of GI physiology highlights)

http://www.kumc.edu/AMA-MSS/study/phys4.htm (more detailed study guide of GI physiology)

We will try to aim for something in between for our GI lectures!

Summary: our food is made up of large biochemical polymers with monomer subunits. Digestion of polymers into monomers occurs by hydrolysis reactions and then absorption in the gastrointestinal tract (GI tract). With the GI tract topologically outside of the body, the active digestive enzymes can go to work in a harsh environment, surrounded by the mucosa and other layers of the gut.

GI tract (alimentary canal): oral (mouth, buccal) cavity, pharynx, esophagus, stomach, small intestine, and large intestine. Accessory organs: teeth, tongue, salivary glands, liver, gall bladder, and pancreas. Our tour down the digestive tract begins with the:

Mouth: mastication of food. Saliva contains water, alpha amylase (ptyalin), mucus, and antimicrobial agents (lysozyme): why are these functions necessary?

Swallowing involves the tongue passing a bolus down the pharynx. This is coordinated so that the soft palate closes, the epiglottis covers the glottis, etc., in a < 2 second timeframe. Involuntary propulsion or peristalsis down the esophagus to the stomach in another 8 seconds or so.⁴ The enteric nervous system contains both myenteric (Auerbach's) and submucosal (Meissner's) plexuses.

Esophagus: a vaguely defined lower esophageal (gastroesophageal) sphincter here (heartburn, when not closing; achalasia, when sphincter fails to relax with decreased innervation).

Stomach: most distensible part of the GI tract. Functions: store food, initiate protein digestion, kill bacteria with gastric acid, move food into small intestine in the form of chyme. Transition time can vary, depending on whether a carbohydrate or fatty meal, and hence, the rate of emptying.

Macroscopic rugae vs. microscopic gastric pits. In the fundic glands:

goblet cells for mucus

parietal cells for HCl, also for intrinsic factor for vitamin B₁₂

chief (zymogenic) cells for pepsinogen

In contrast, pyloric glands have the mucous cells and …

G cells for gastrin (a hormone which stimulates acid production)

The parietal cells secrete H⁺ via a H⁺-K⁺ ATPase, coupled with a Cl^--HCO₃^- exchanger on their basolateral membrane, so that net: HCl to lumen, HCO₃^- to bloodstream. The low pH of the stomach helps to denature proteins and activate the protease pepsin. Carbohydrates and fats are barely digested in the stomach (a -amylase inhibited by acidity). Most digestion products are absorbed through the walls of the small intestine. Commonly ingested items that are absorbed through the stomach wall are alcohol and aspirin, because of their lipid solubility.

peptic ulcer: erosion of mucus membrane of stomach/duodenum. In the (rare) Zollinger-Ellison syndrome, duodenal ulcers seen with excessive acid secretion from high levels of gastrin, i.e., normal acid alone typically doesn't cause an ulceration unless there's a predisposing factor. Helicobacter pylori: association with gastritis and peptic ulcers. H. pylori infections respond to a combination of antibiotics (tetracycline) and agents such as bismuth salicylate products that help to negate the environment that the bacterium thrives in.⁵

Histamine stimulates the ATPase via receptor stimulation and cAMP second messenger, so a blockage of the H₂ histamine receptors in gastric mucosa should offer relief for peptic ulcer patients, e.g., cimetidine (Tagamet). Other pharmacologic intervention could include omezaprole (Prilosec) for inhibition of the proton pump.

Parietal and chief cells are very impermeable to the acid of the gastric lumen, as well as to CO₂ and NH₃. Other protective approaches:³

1. layer of alkaline mucus containing bicarbonate
2. rapid cell division for replacement, e.g., the entire epithelium replaces itself in 3 days.
3. gastric mucosa also produces prostaglandins for self defense (so that NSAIDs can help to cause ulcers by inhibiting this prostaglandin production).

vomiting: reverse peristalsis, from activation of sensory receptors and messages sent to vomiting center in the medulla, e.g., from CTZ (chemoreceptor trigger zone).² Multiple cranial nerves are involved (why?), with cessation of respiration, a forceful contraction of abdominal muscles (why?) for this useful physiological defense. Loss of HCl from vomiting can lead to a metabolic alkalosis and a hypochloremia. Normally, the HCO₃^- produced 2^o to the proton pump would be"recycled" with neutralization of chyme.

Small intestine: 25 cm of duodenum, 40% jejunum, 60% ileum.

Facing the acidic chyme of the stomach, the duodenum is usually protected by buffering from:

1) alkaline pancreatic juice containing bicarbonate

2) bicarbonate secretion from Brunner's glands in duodenal submucosa

The small intestine has more of a mixing segmentation movement than the propulsion-type movement of peristalsis (as befitting its digestive, absorptive role), with a transit time of 2-4 hours.¹ This intestinal smooth muscle activity is established first by pacemaker smooth muscle cells that spontaneously depolarize to form slow waves of pacesetter potentials. Localized action potentials then would create the churning of segmentation

The overall function of the small intestine includes:

The small intestine shows many levels of increasing surface area for these roles:

a) microvilli, b) villi, c) plicae circularles, d) long length

Villus(-i): fingerlike fold of mucosa, with capillaries and a central lymphatic lacteal (to pick up the chylomicrons of fatty acids). Cell membranes contain digestive brush border enzymes, with active sites facing out. Examples of these brush border enzymes include:

enterokinase, to activate the trypsin from pancreatic juice

lactase, at least present in young children

The small intestine absorbs most of the 7-9 L of fluid secreted by other digestive organs, with the large intestine for"fine tuning" of the fluid in the forming feces.

Carbohydrates are"finished off" in the small intestine with pancreatic amylase producing oligosaccharides then and further clipping with brush border enzymes. Monosaccharides can then be co-transported with Na⁺ into intestinal cells.

Proteins are initially hydrolyzed by pepsin, but pancreatic juice enzymes and peptidase brush border enzymes are specialized for different parts of the amino acid sequences to produce amino acids, di- and tripeptides, which are then carried across the epithelium. Cytosolic peptidases can finish the digestion to single amino acids.⁴

Lipids are emulsified with bile and then digested with pancreatic lipase into fatty acids and monoglycerides. Epithelial cells take these up, resynthesize triglycerides to form chylomicrons that then travel in the lacteals of the villi. I presume you are familiar with transport of chylomicrons in the bloodstream--if not, let's reacquaint ourselves with HDLs, LDLs, and VLDLs.

Large intestine: The large intestine absorbs water and electrolytes from the chyme, and passes waste out of the body, with the large intestine facing 2 L of fluid and reabsorbing all but 100 ml of that into the feces. As part of this final fluid"tuning," there is a net additional reabsorption of sodium, with excretion of bicarbonate (as a result of the need to buffer acidic bacterial products, respectively).⁴ Diarrhea can therefore lead to a metabolic acidosis. The waste's that's left goes to the rectum, where there is an increase in rectal pressure and an urge to defecate. The internal anal sphincter keeps the feces from entering the anal canal, with a voluntary external anal sphincter as the final arbiter.

diarrhea: excessive fluid excretion with the feces. The small intestine has a greater capacity for absorption/secretion than does the large intestine, so it can be a major contributor to diarrheal issues. Several diarrheal diseases/mechanisms:

constipation: infrequent, hard stools, e.g., from lack of stool bulk (Metamucil, anyone?), decreased peristalsis.

irritable bowel syndrome (IBS): apparent supersensitivity to distension in large intestine.⁶

Liver: The liver, the largest internal organ, and on its inferior surface, the gall bladder. The hepatocytes form hepatic plates separated by sinusoids. The portal triad in connective tissue help to define acini that drain into the central veins. This interpretation of liver function helps to explain zones of destruction around the central veins, as compared to the interpretation of lobule units.

The blood of the portal vein runs in sinusoids between hepatic plates. Hepatic artery blood also runs through sinusoids so that the arterial and venous blood mixes along the way.

Bile, produced by the hepatocytes, is secreted into channels called bile canaliculi, which run within each hepatic plate. These canaliculi travel toward the bile ducts, so that the bile and blood flow in opposite directions and do not mix.

cirrhosis: acini are destroyed and replaced with connective tissue and regenerative nodules of hepatocytes. These do not have the platelike structure and are less functional, e.g., more ammonia into system and portal hypertension.

Liver function includes the following:

Bile production and secretion. 250-1500 ml of bile per day. Major components of bile include: bile salts for fat solubilization, bile pigments (bilirubin) for excretion.

Bile salts are cholesterol derivatives, principally cholic acid and chenodeoxycholic acid. Bile salts form micelles, with the polar groups facing outward. Lecithin, cholesterol, and other lipids in the small intestine enter the micelles to aid the digestion and absorption of fats.

The liver can conjugate some of the free bilirubin with glucuronic acid to from a water-soluble conjugated bilirubin that is water-soluble and can be secreted into bile. If it is in the bile and enters the intestine, the conjugated bilirubin can be modified by the intestinal flora to urobilinogen, which gives helps to give color to the feces. Some of the urobilinogen can also be reabsorbed and enter the general circulation. Unattached to albumin, the urobilinogen can be filtered and so gives urine a nice yellow. This highlights an enterohepatic circulation, where bile and bile products secreted into the small intestine can be reuptaken by the portal vein circulation (in the ileum, right?), remetabolized by the liver, etc.²

jaundice: yellow staining of tissues produced by high blood levels of free or conjugated bilirubin. Possibilities of:

1. prehepatic or hemolytic jaundice
2. intrahepatic jaundice
3. posthepatic or obstructive jaundice

Detoxification of blood: The liver can remove bioactive molecules by:³

1. excretion of compounds in bile
2. phagocytosis by Kupffer cells that line the sinusoids
3. chemical alteration of molecules within hepatocytes, e.g., NH₃ removed by liver, with enzymes converting it to less toxic urea

Steroid hormones and other drugs are inactivated by the liver by chemical modification, e.g., polarizing them by hydroxylation and/or by conjugation with polar groups such as sulfate and glucuronic acid. These changes make the molecules less active and more likely to be excreted. Cytochrome P450 enzymes in the liver (as part of what organelle?) that can metabolize many different toxic compounds. P450 levels vary individually, so differing sensitivities to drugs among the population. Plasma albumin and most of the plasma globulins (not immunoglobulins) are produced by liver. Albumin is 70% of total plasma protein and accounts for most of the colloid oncotic pressure.

Gall bladder: stores and concentrates bile. Contraction of the muscularis layer of the gall bladder ejects bile into the common bile duct. Gallstone: typically cholesterol as a major component. Cholesterol has a low solubility, but is clustered in the hydrophobic middle of micelles. If these precipitate, then gallstones form. Oral ingestion of bile acids can be therefore one approach to breaking up gallstones, in addition to surgery, interventional radiology, or extraorporeal shock-wave lithotripsy.

Pancreas: an accessory organ with both exocrine and endocrine functions.

exocrine: secretory units of acini, or a layer of epithelial cells surrounding a lumen, which secretes components of pancreatic juice.

endocrine: pancreatic islets (of Langerhans) that secrete insulin and glucagon (next week)

Pancreatic juice ingredients include: water, bicarbonate, and digestive enzymes:

amylase for starch; trypsin for protein; lipase for triglyceride

Most pancreatic enzymes are produced as inactive zymogens (cuts down on risk of self-digestion of pancreas), e.g., trypsinogen activated by brush border enzyme enterokinase into trypsin. Trypsin then activates other zymogens by cleaving off polypeptide sequences. Some of the trypsin in the pancreas is active, but inhibited by pancreatic trypsin inhibitor.

acute pancreatitis: e.g., from reflux of pancreatic juice and bile from the duodenum.

HORMONES: BASIS OF ACTION

Endocrine glands produce hormones, or chemicals produced by one cell and that affect the metabolism of another cell in small amounts. Hormones accomplish this in two ways:

1. a water-soluble hormone (polypeptide) binds to a receptor on the target cell surface and sets off a secondary messenger to change the cell activities (quick onset of action).
2. a fat-soluble steroid or thyroid hormone, being nonpolar, passes through the target cell plasma membrane, binds with a receptor in the cytoplasm or nucleus (thyroid hormone), and the resulting hormone-receptor complex interacts with the DNA directly (slower onset of action).

Endocrine glands lack ducts and so secrete their hormones directly into the blood. In order to find its target, it must have:

1. target cells with specific receptor proteins that combine with the hormone
2. receptor-hormone complex must cause a specific sequence of changes in target cells
3. a mechanism to quickly turn off the action of the hormone

Receptors in target cells must have: specificity, high affinity, and low capacity (i.e., saturable). A particular target tissue may respond to different hormones or combination of hormones.

As hormones circulate, the free (unbound) hormone is biologically active. Hormones bound to carrier proteins (e.g., 90% of nonpolar steroid and thyroid hormones) cannot interact with the receptors. Hormones do not generally accumulate in the blood since they are rapidly removed by target organs and the liver, so that the half-life runs from minutes to hours (days for thyroid hormone).²

One can often have a priming effect on the target cells. More receptors can be formed on target cells, or up-regulation.

In contrast, one can have desensitization of target cells in response to prolonged exposure to polypeptide hormones, from downregulation of the number of receptor proteins. To avoid this, many polypeptide and glycoprotein hormones are secreted in a pulsatile fashion.

gastrointestinal hormones (polypeptides):

Gastric motility and secretion are mostly automatic, but the effect of autonomic nerves and hormones are superimposed on this. This control of gastric function has three aspects:

1. cephalic phase (vagal nerve stimulation from CNS)
2. gastric phase (positive feedback from stomach)
3. intestinal phase (stimulation of hormones when chyme reaches intestine)

1. J Bullock, et al., Physiology, 3^rd ed. (Williams & Wilkins, Philadelphia, 1995), pp. 433, 445.
2. DH Cormack, Clinically Integrated Histology (Lippincott-Raven, Philadelphia, 1998), pp. 197, 208.
3. SI Fox, Human Physology, 6^th ed. (WCB McGraw-Hill, Boston, 1999), pp. 290 , 571, 572, 584.
4. AC Guyton, JE Hall, Textbook of Medical Physiology, 9^th ed. (WB Saunders, Philadelphia, 1996), pp. 805, 835, 843.
5. JM Henderson, Gastrointestinal Pathophysiology ((Lippincott-Raven, Philadelphia, 1996), pp. 39, 50.
6. RA Rhoades, GA Tanner, Medical Physiology (Little, Brown, and Company, Boston, 1995), pp. 500-501.

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